The overall object of this application is to explore the possibility that human DNA ligase I could be a potential target in anticancer therapy by investigating the relationship between DNA ligase I expression and the neoplastic process. Human DNA ligase I is an essential enzyme required during DNA replication, transcription, repair, and recombination by joining single- and double-stranded DNA with the formation of phosphodiester bonds. There is compelling evidence that human DNA ligase I is much more active in rapidly proliferating cells such as tumor cells. This suggests that DNA ligase I could be a very interesting and unique target for anticancer agents and that there is a very strong possibility for achieving the selectivity against rapidly proliferating tumor cells by using DNA ligase I-interactive agents. The applicant proposes to test the hypothesis that human DNA ligase I expression is tightly related to the neoplastic process, and targeting human DNA ligase I offers a potential for enhanced therapeutic benefit. The following specific aims are proposed: 1) Assess human DNA ligase I levels in human tumors versus normal tissue. 2) Investigate the regulatory mechanisms of human DNA ligase I gene expression. 3) Test whether DNA ligase I inhibition produces antitumor activity using antisense strategy in preclinical in vitro and in vivo evaluation systems. 4) Develop a sensitive and reproducible assay for DNA ligase I.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
7R29CA078715-05
Application #
6591545
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Hagan, Ann A
Project Start
1998-08-05
Project End
2003-07-31
Budget Start
2002-03-16
Budget End
2002-07-31
Support Year
5
Fiscal Year
2001
Total Cost
$36,360
Indirect Cost
Name
University of Arizona
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85721